MARVEL on RT mutations at position 184

HIVdb Algorithm: Comments & Scores

M184V/I cause high-level resistance to 3TC and FTC and low-level resistance to ddI and ABC. However, M184V/I are not contraindications to continued treatment with 3TC or FTC because they increase susceptibility to AZT, TDF and d4T and are associated with clinically significant reductions in HIV-1 replication. In combination with K101E or E138K, M184I synergistically reduces RPV susceptibility.

Mutation

3TC

FTC

ABC

AZT

D4T

DDI

TDF

M184I

60

60

15

-10

-10

10

-10

M184V

60

60

15

-10

-10

10

-10

Footnote:Mutation scores on the left are derived from published literature linking mutations and ARVs (the complete details can be found in the HIVdb Release Notes).

Genotype-treatment correlation

Mutation frequency according to subtype and drug-class experience.

The frequency of each mutation at position 184 according to subtype and drug-class experience. Data are shown for the 8 most common subtypes. The number of persons in each subtype/treatment category is shown beneath the subtype. Mutations occurring at a frequency >0.5% are shown. Each mutation is also a hyper-link to a separate web page with information on each isolate, including literature references with PubMed abstracts, the GenBank accession number, and complete sequence and treatment records.

The first row shows the frequency of the mutation in persons who are RTI-naive (indicated in green). The second row shows the frequency of the mutation in persons who have received one or more NRTIs (+/- NNRTIs). The following rows show the frequency of the mutation in persons who have received only a single NRTI. Mutation rates that differ significantly between treated and untreated isolates are indicated in yellow.

Mutation

NRTI

NNRTI

NumSeq

NumMut

% Mutant

p

M184I

0

0

56414

20

0.00

M184I

>=1

>=0

26254

476

1.80

0.000

M184I

AZT

>=0

453

1

0.20

0.414

M184I

DDI

>=0

53

0

M184I

D4T

>=0

55

0

M184I

ABC

>=0

47

0

M184I

D4T+3TC

>=0

3574

96

2.60

0.000

M184I

AZT+3TC

>=0

2669

27

1.00

0.000

M184I

D4T+DDI

>=0

462

2

0.40

0.002

M184I

AZT+DDI

>=0

582

1

0.10

0.535

M184I

ABC+3TC

>=0

326

11

3.30

0.000

M184I

TDF+3TC

>=0

459

50

10.80

0.000

M184I

TDF+FTC

>=0

378

33

8.70

0.000

Mutation

NRTI

NNRTI

NumSeq

NumMut

% Mutant

p

M184L

0

0

56414

12

0.00

M184L

>=1

>=0

26254

10

0.00

0.250

M184L

AZT

>=0

453

0

M184L

DDI

>=0

53

0

M184L

D4T

>=0

55

0

M184L

ABC

>=0

47

0

M184L

D4T+3TC

>=0

3574

1

0.00

0.748

M184L

AZT+3TC

>=0

2669

1

0.00

0.906

M184L

D4T+DDI

>=0

462

0

M184L

AZT+DDI

>=0

582

0

M184L

ABC+3TC

>=0

326

0

M184L

TDF+3TC

>=0

459

0

M184L

TDF+FTC

>=0

378

0

Mutation

NRTI

NNRTI

NumSeq

NumMut

% Mutant

p

M184T

0

0

56414

3

0.00

M184T

>=1

>=0

26254

12

0.00

0.000

M184T

AZT

>=0

453

1

0.20

0.008

M184T

DDI

>=0

53

0

M184T

D4T

>=0

55

0

M184T

ABC

>=0

47

0

M184T

D4T+3TC

>=0

3574

0

M184T

AZT+3TC

>=0

2669

0

M184T

D4T+DDI

>=0

462

0

M184T

AZT+DDI

>=0

582

0

M184T

ABC+3TC

>=0

326

0

M184T

TDF+3TC

>=0

459

0

M184T

TDF+FTC

>=0

378

0

Mutation

NRTI

NNRTI

NumSeq

NumMut

% Mutant

p

M184V

0

0

56414

119

0.20

M184V

>=1

>=0

26254

13308

50.60

0.000

M184V

AZT

>=0

453

3

0.60

0.119

M184V

DDI

>=0

53

9

16.90

0.000

M184V

D4T

>=0

55

0

M184V

ABC

>=0

47

17

36.10

0.000

M184V

D4T+3TC

>=0

3574

2648

74.00

0.000

M184V

AZT+3TC

>=0

2669

1699

63.60

0.000

M184V

D4T+DDI

>=0

462

12

2.50

0.000

M184V

AZT+DDI

>=0

582

12

2.00

0.000

M184V

ABC+3TC

>=0

326

163

50.00

0.000

M184V

TDF+3TC

>=0

459

233

50.70

0.000

M184V

TDF+FTC

>=0

378

120

31.70

0.000

Footnote: About one-half of the untreated isolates belong to non-subtype B isolates; About 20% of the treated isolates belong to non-subtype B isolates; A page containing summaries for all of the mutations at this position can be found here.

Genotype-phenotype correlation

Phenotypes of top 10 common patterns of drug resistance mutations with mutations at position 184.

Mutation patterns are listed in the frequency with which they have been reported in the published literature. The median level of fold resistance (compared with wildtype) for viruses with the mutation pattern in the first column are indicated when available. The subscripts indicate the number of viruses that were phenotyped. The drug susceptibility assay used was the PhenoSense assay (Monogram, South San Francisco). A hyperlink for each individual pattern is provided to access a complete list of mutations and fold resistances for each sequence matching the pattern of mutation.

A complete summary of additional in vitro susceptibility data for viruses with M184 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with M184 (not just the top 10 most frequent patterns) can be found at this page.

Footnote: Mutation patterns were defined by the presence or absence of major NRTI drug resistance mutations ; Sequences containing a mixture at a major drug resistance positions were excluded; For the cutoffs defined by PhenoSense, open the sample report form provided on this page; The full list of all mutation patterns are also available here.

Phenotypic coefficients using machine learning

Least Square Regression (LSR) was used to learn the relative contribution of each mutation to the fold decrease in susceptibility for an ARV. The figure on the left (click to enlarge the figure) shows the regression coefficients (which correlate with the contribution to resistance) for the 23 nonpolymorphic NRTI-resistance mutations shown to contribute decreased susceptibility to at least one NRTI. A complete description of the method that generates this figure can be found at Rhee et al PNAS 2006.

Genotype-clinical outcome correlation

Studies correlating baseline genotype and virological response to an ARV therapy with or without mutations at 184.

Hydroxyurea + ddI led to a greater RNA decrease than ddI alone at week 8 (~1.8 vs 0.8 logs). The combination was associated with a sustained response ~1.2-1.6 logs at week 24. At week 8, there was a greater reduction in RNA in the NRTI-na´ve group (1.7 vs 1.2 logs) but there was little difference in response between those with M184V (1.2 logs in 18 3TC-experienced patients with M184V vs 1.4 logs in 61 3TC-na´ve patients).

Observational study. Overall RNA decrease was 1.2, 1.0, 0.8, and 0.8 at weeks 4, 12, 24, and 48. There was no significant difference in RNA response between the 105 pts with and the 176 pts without M184V.

M41L, E44D/A/G, T69D/S/N/A, L210W, T215Y or T215 revertants, and L228H/R were associated with a reduced RNA decrease. D123E/N/G/S was associated with improved virological response. The following weighted score was derived: (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y revertants + L228H/R - D123E/N/G/S. Relative to those with a score <=0, those with a score of 1 to 3 had a 0.34 decreased log RNA response and those with a score >=4 had a 0.68 decreased RNA log response.

Among pts receiving TDF, there was a mean 0.6 log RNA decrease at week 24 by ITT. Pts with 215Y/F alone had a 0.7 log RNA decrease. Pts with M41L+L210W + T215Y had a 0.2 log RNA decrease. Mutations at positions 67, 70, and 219 did not appear to affect response. K65R was present at baseline in 6 pts and was associated with lack of response. M184V was associated with a modest but significant improved response particularly in the absence of TAMs.